The present invention relates to new optically active salts obtained from a substituted thiazolidine-4-carboxylate and 3-cyano-2-hydroxypropyl trimethylammonium, their production and uses thereof. A preferred aspect of the invention relates to obtaining of L-(-)-3-cyano-2-hydroxypropyl trimethylammonium chloride (L-carnitine nitrile chloride), a valuable constituent for the synthesis of L-carnitine.
L-carnitine, also known as vitamin B.sub.T, is increasingly being used in dietetic and pharmaceutical preparations for the treatment of injured myocardia, chronic circulatory disturbances, as well as for increasing functional capacity. Most chemical processes for the production of L-carnitine involve racemate resolution of a carnitine precursor. A racemate resolution of the precursor D,L-carnitine amide by using an optically active acid is known (East German Patent DD-PS 23217, German Published Patent Applications DE-OS 29 27 672, DE-OS 33 42 713). It is especially disadvantageous that D,L-carnitine amide must first specifically be produced from D,L-carnitine nitrile chloride. Compared to a racemate resolution at the D,L-carnitine nitrile chloride stage, which can be directly saponified to carnitine, an additional reaction stage is required.
Common features of a racemate resolution of D,L-carnitine nitrile chloride, the production of which generally is performed by the cyaniding of D,L-3-chloro-2-hydroxypropyl trimethylammoniumchloride or D,L-epoxypropyl trimethylammoniumchloride, are the conversion of the chloride into the hydroxide, reaction with an optically active acid, separation of the diastereomeric salts and the separation of the same with a strong acid. As a result, the optically active carnitine nitrile salt is obtained and the introduced optically active acid is recovered.
As an optically active acid for the racemate resolution of carnitine nitrile chloride there were proposed, for example, D-tartaric acid and D-camphor-10-sulfonic acid. However, minor differences in solubility made frequent recrystallization of the diastereomeric salts necessary. The combined use of D-camphor-10-sulfonic acid and dibenzoyl-L-tartaric acid (E. Strack et al., Z. physiol, Chem 318, 129 (1960)) provided an improvement. However, the use of two resolution agents results in high costs and make the process unsuitable for industrial application. With exclusive use of dibenzoyl-L-tartaric acid, the difference in solubility for both diastereomers is small, which again affects the yield.
The use of optically active N-acetyl-glutamic acid as resolution acid (Japanese Patent JP-B 43-8248, Dutch Patent NL-A 6614321) has also become known. In order to obtain the L-carnitine nitrile salt, there is required not the naturally occurring N-acetyl-L-glutaminic acid, but its antipode N-acetyl-D-glutaminic acid. The latter is not independently present in sufficient quantity, however, and must be produced by using D-carnitine nitrile chloride. However, if the slightly soluble salt of D-carnitine nitrile and N-acetyl-L-glutaminic acid is first separated from the diastereomeric pair, obtaining an optically pure L-carnitine-N-acetyl-D-glutamate from the mother liquor requires a multiple fractionating crystallization.
In order to improve the efficiency of the above-mentioned resolution reagents and to increase the optical purity of the desired carnitine nitrile salt, it was suggested to subsequently add an additional fractionating crystallization of a salt from the initially obtained optically active carnitine nitrile hydroxide and an optically inactive acid, such as oxal acid or perchloro acid (JP-A 62-286959). The entire process effort was, however, increased significantly. The racemate resolution using exclusively fractionating crystallization of D,L-carnitine nitrile oxalate or perchlorate only provides small chemical and optical yields (French Patent Applications FR-A 2 529 545, FR-A 2 536 391).
Processes for racemate resolution of D,L-3-chloro-2-hydroxypropyl trimethylammonium chloride, i.e., the precursor to D,L-3-cyano-2-hydroxypropyl trimethylammonium chloride, have also become known. According to European Patent Application EP-A 312 726, tartaric acid was used as the separation reagent. The tartaric acid, however, leaves much to be desired as a resolution reagent for technological purposes, because of its water solubility. Thus, it can only be recovered with much difficulty from the aqueous solutions that are obtained during the release of the L- or D,L-3-chloro-2-hydroxypropyl trimethylammonium chloride from the diastereomeric salt. Furthermore, the yield is not satisfactory due to irreversible side reactions, among other things.
Optical salts from a substituted thiazolidine-4-carboxylate and 3-chloro-2-hydroxypropyl trimethylammonium are known from European Patent Application EP-A 312 726. These salts are produced from a substituted optically active thiazolidine-4-carbonic acid that is first converted to the trimethylammonium salt by means of trimethylamine and subsequently is reacted with epichlorohydrin. The resulting diastereomeric salt pairs exhibit pronounced different solubilities, so that they can be separated through fractionation crystallization. By means of acid separation of the salt pair, L-(-)-3-chloro-2-hydroxy trimethylammonium chloride can be obtained, which can be converted to the 3-cyano compound and by way of hydrolysis to L-(-)-carnitine.
Although this method has the advantage that during the reaction, apart from the desired L-(-)-3-chloro-2-hydroxypropyl ammonium chloride, the produced undesirable D-enantiomerics as well as the racemic form can be utilized for cationization purposes, in practice, this entails some drawbacks. Thus, the reaction with trimethylamine and epichlorohydrin requires an extraordinarily high degree of technological efforts due to annoying odors in connection therewith and the high toxicity. Also, traces of non-reacted starting materials must be separated from the system and disposed of in a safe manner. The effort needed for the technological measures, e.g., steam distillation, including necessary safety measures for the contact with epichlorohydrin and the like, quickly exceed the utility of being able to utilize the D-enantiomers.
An object of the present invention is to eliminate the drawbacks of the known methods for producing the optically active 3-cyano-2-hydroxy trimethylammonium chloride necessary for the carnitine synthesis.
A further object is to provide optically active salts that can be produced in a simple and economical manner and that are suitable for racemate resolution of the cation of the salts, i.e., the D,L-3-cyano-2-hydroxy-trimethylammonium, practically without any loss of the optically active anion of these salts.